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Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia

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Item Type:Article
Title:Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia
Creators Name:Wallach, T., Raden, M., Hinkelmann, L., Brehm, M., Rabsch, D., Weidling, H., Krüger, C., Kettenmann, H., Backofen, R. and Lehnardt, S.
Abstract:INTRODUCTION: The pandemic coronavirus disease 19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is marked by thromboembolic events and an inflammatory response throughout the body, including the brain. METHODS: Employing the machine learning approach BrainDead we systematically screened for SARS-CoV-2 genome-derived single-stranded (ss) RNA fragments with high potential to activate the viral RNA-sensing innate immune receptors Toll-like receptor (TLR)7 and/or TLR8. Analyzing HEK TLR7/8 reporter cells we tested such RNA fragments with respect to their potential to induce activation of human TLR7 and TLR8 and to activate human macrophages, as well as iPSC-derived human microglia, the resident immune cells in the brain. RESULTS: We experimentally validated several sequence-specific RNA fragment candidates out of the SARS-CoV-2 RNA fragments predicted in silico as activators of human TLR7 and TLR8. Moreover, these SARS-CoV-2 ssRNAs induced cytokine release from human macrophages and iPSC-derived human microglia in a sequence- and species-specific fashion. DISCUSSION: Our findings determine TLR7 and TLR8 as key sensors of SARS-CoV-2-derived ssRNAs and may deepen our understanding of the mechanisms how this virus triggers, but also modulates an inflammatory response through innate immune signaling.
Keywords:SARS-CoV-2, RNA, Toll-Like Receptors, iPSC-Derived Human Microglia, Macrophages, Inflammatory Response, Animals, Mice
Source:Frontiers in Immunology
ISSN:1664-3224
Publisher:Frontiers Media SA
Volume:13
Page Range:1066456
Date:13 January 2023
Official Publication:https://doi.org/10.3389/fimmu.2022.1066456
PubMed:View item in PubMed

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